MSGID: 1:317/3 64475769   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    New biologic effective against major infection in early tests    
      
     Date:   
         April 24, 2023   
     Source:   
         NYU Langone Health / NYU Grossman School of Medicine   
     Summary:   
         A research team has shown in early tests that a bioengineered   
         drug candidate can counter infection with Staphylococcus aureus --   
         a bacterial species widely resistant to antibiotics.   
      
      
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   FULL STORY   
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   Researchers at NYU Grossman School of Medicine and Janssen Biotech,   
   Inc. have shown in early tests that a bioengineered drug candidate   
   can counter infection with Staphylococcus aureus -- a bacterial species   
   widely resistant to antibiotics and a major cause of death in hospitalized   
   patients.   
      
   Experiments demonstrated that SM1B74, an antibacterial biologic agent, was   
   superior to a standard antibiotic drug at treating mice infected with S.   
      
   aureus, including its treatment-resistant form known as MRSA.   
      
   Published online April 24 in Cell Host & Microbe,the new paper   
   describes the early testing of mAbtyrins, a combination molecule   
   based on an engineered version of a human monoclonal antibody (mAb),   
   a protein that clings to and marks S. aureus for uptake and destruction   
   by immune cells. Attached to the mAb are centyrins, small proteins that   
   prevent these bacteria from boring holes into the human immune cells in   
   which they hide. As the invaders multiply, these cells die and burst,   
   eliminating their threat to the bacteria.   
      
   Together, the experimental treatment targets ten disease-causing   
   mechanisms employed by S. aureus, but without killing it, say the study   
   authors. This approach promises to address antibiotic resistance, say   
   the researchers, where antibiotics kill vulnerable strains first, only   
   to make more space for others that happen to be less vulnerable until   
   the drugs no longer work.   
      
   "To our knowledge, this is the first report showing that mAbtyrins   
   can drastically reduce the populations of this pathogen in cell   
   studies, and in live mice infected with drug-resistant strains so   
   common in hospitals," said lead study author Victor Torres, PhD,   
   the C.V. Starr Professor of Microbiology and director of the NYU   
   Langone Health Antimicrobial-Resistant Pathogen Program."Our goal was   
   to design a biologic that works against S. aureus inside and outside   
   of cells, while also taking away the weapons it uses to evade the   
   immune system."  One-third of the human population are carriers of   
   S. aureus without symptoms, but those with weakened immune systems may   
   develop life-threatening lung, heart, bone, or bloodstream infections,   
   especially among hospitalized patients.   
      
   Inside Out The new study is the culmination of a five-year research   
   partnership between scientists at NYU Grossman School of Medicine and   
   Janssen to address the unique nature of S. aureus.   
      
   The NYU Langone team together with Janssen researchers, published in 2019   
   a study that found that centyrins interfere with the action of potent   
   toxins used by S. aureus to bore into immune cells. They used a molecular   
   biology technique to make changes in a single parental centyrin, instantly   
   creating a trillion slightly different versions of it via automation. Out   
   of this "library," careful screening revealed a small set of centyrins   
   that cling more tightly to the toxins blocking their function.   
      
   Building on this work, the team fused the centyrins to a mAb originally   
   taken from a patient recovering fromS. aureusinfection. Already primed   
   by its encounter with the bacteria, the mAb could label the bacterial   
   cells such that they are pulled into bacteria-destroying pockets inside   
   of roving immune cells called phagocytes. That is unless the same toxins   
   that enable S. aureus to drill into immune cells from the outside let   
   it drill out of the pockets to invade from the inside.   
      
   In a "marvel of bioengineering," part of the team's mAbtyrin serves   
   as the passport recognized by immune cells, which then engulf the   
   entire, attached mAbtyrin, along with its centyrins, and fold it into   
   the pockets along with bacteria. Once inside, the centyrins block the   
   bacterial toxins there. This, say the authors, sets their effort apart   
   from antibody combinations that target the toxins only outside of cells.   
      
   The team made several additional changes to their mAbtyrin that defeat S.   
      
   aureus by, for instance, activating chain reactions that amplify the   
   immune response, as well by preventing certain bacterial enzymes from   
   cutting up antibodies and others from gumming up their action.   
      
   In terms of experiments, the researchers tracked the growth of S. aureus   
   strains commonly occurring in US communities in the presence of primary   
   human immune cells (phagocytes). Bacterial populations grew almost   
   normally in the presence of the parental antibody, slightly less well   
   in the presence of the team's engineered mAb, and half as fast when the   
   mAbtyrin was used.   
      
   In another test, 98% of mice treated with a control mAb (no centyrins)   
   developed bacteria-filled sores on their kidneys when infected with a   
   deadly strain of S. aureus, while only 38% of mice did so when treated   
   with the mAbtyrin. Further, when these tissues were removed and colonies   
   of bacteria in them counted, the mice treated with the mAbtyrin had one   
   hundred times (two logs) fewer bacterial cells than those treated with   
   a control mAb.   
      
   Finally, the combination of small doses of the antibiotic vancomycin with   
   the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin,   
   resulting in maximum reduction of bacterial loads in the kidneys and   
   greater than 70% protection from kidney lesions.   
      
   "It is incredibly important," said Torres, "that we find new ways to   
   boost the action of vancomycin, a last line of defense against MRSA."   
   Along with Torres, authors from the Department of Microbiology at NYU   
   Langone were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O'Malley,   
   and Anna O'keeffe.   
      
   The study authors included 13 scientists from Janssen Research &   
   Development (for details see the study manuscript).   
      
   This work was supported by Janssen Biotech, Inc., one of the Janssen   
   Pharmaceutical Companies of Johnson & Johnson, under the auspices of an   
   exclusive license and research collaboration agreement with NYU. Torres   
   has recently received royalties and consulting compensation from Janssen   
   and related entities. These interests are being managed in accordance   
   with NYU Langone policies and procedures.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Immune_System # Lymphoma # HIV_and_AIDS #   
                   Pharmaceuticals   
             o Plants_&_Animals   
                   # Bacteria # Microbes_and_More # Mice #   
                   Biotechnology_and_Bioengineering   
       * RELATED_TERMS   
             o Antibiotic_resistance o Toxic_shock_syndrome o Drug_discovery   
             o Encephalitis o Penicillin-like_antibiotics o HIV_test o   
             Urinary_tract_infection o Pneumonia   
      
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   Story Source: Materials provided by   
   NYU_Langone_Health_/_NYU_Grossman_School_of_Medicine.   
      
   Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Peter T. Buckley, Rita Chan, Jeffrey Fernandez, Jinquan Luo,   
      Keenan A.   
      
         Lacey, Ashley L. DuMont, Aidan O'Malley, Randall J. Brezski,   
         Songmao Zheng, Thomas Malia, Brian Whitaker, Adam Zwolak, Angela   
         Payne, Desmond Clark, Martin Sigg, Eilyn R. Lacy, Anna Kornilova,   
         Debra Kwok, Steve McCarthy, Bingyuan Wu, Brian Morrow, Jennifer   
         Nemeth-Seay, Ted Petley, Sam Wu, William R. Strohl, Anthony Simon   
         Lynch, Victor J. Torres.   
      
         Multivalent human antibody-centyrin fusion protein to prevent and   
         treat Staphylococcus aureus infections. Cell Host & Microbe, 2023;   
         DOI: 10.1016/j.chom.2023.04.004   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/04/230424133548.htm   
      
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